DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s submission filed 10/20/2025 has been received and entered. Claims 6, 10, 17, 19, 21-23, 25 and 30-35 have been cancelled. Claims 1, 7-8, 14-15 and 18 have been amended. Accordingly, claims 1, 2, 4, 7-8, 14-15, 18 and 20 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to the Abstract is withdrawn:
Applicant’s submission of Abstract on a separate page is effective to obviate the prior basis of the objection. The objection is withdrawn.
The objection to the Drawings is maintained:
Applicant’s submission includes a single sheet of a clear version of figure 1G. However, it is required that any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. See MPEP 608.02(e). Therefore the objection is maintained and modified in view of Applicant’s submission of the replacement drawing.
The objection to claim 15 is withdrawn:
Applicant’s amendment to claim 15 adds the sequence identifier number SEQ ID NO:13, the amendment is effective to obviate the prior basis of the objection. The objection is withdrawn.
The rejection of claims 1, 17 and 20 under 35 U.S.C. § 102(a)(2) over Bell et al., as evidenced by Hamza et al. is withdrawn:
Applicant’s cancellation to claim 17 render the rejection thereto moot. The rejection to claim 17 is withdrawn.
Regarding claim 1 and 20, Applicant’s amendment to claim 1 adds the limitation that the second polypeptide comprises an IL-12p40 polypeptide sequence, a polypeptide linker, and a membrane anchoring polypeptide sequence, wherein said nucleic acid encoding said first polypeptide is operably linked to a promoter capable of driving transcription of a polycistronic transcript comprising said nucleic acid encoding said first polypeptide, an internal ribosome entry site (IRES), and said nucleic acid encoding said second polypeptide, and wherein said membrane anchoring polypeptide sequence comprises a polypeptide capable of a glycosylphosphatidyl-inositol (GPI) modification. Bell et al. as evidenced by Hamza et al. do not teach this limitation. Therefore applicant’s amendment is effective to obviate the prior basis of the rejection. The rejection is withdrawn.
The rejection of claims 1, 6-8, 10, 14-15 and 17-20 under 35 U.S.C. § 103 over Bell et al., as evidenced by Hamza et al. in view of Guo et al. is maintained:
The rejection of claims 1, 2, 4, 17 and 20 under 35 U.S.C. § 103 over Bell et al., as evidenced by Hamza et al. in view of Wagner et al. is maintained:
Applicant’s cancellation to claims 6, 10, 17 and 19 render the rejection thereto moot. The rejection to claims 6, 10, 17 and 19 is withdrawn.
Regarding claims 1, 2, 4, 7, 8, 14, 15, 18 and 20, Applicant’s amendment to claim 1 adds the limitation that the second polypeptide comprises an IL-12p40 polypeptide sequence, a polypeptide linker, and a membrane anchoring polypeptide sequence, wherein said nucleic acid encoding said first polypeptide is operably linked to a promoter capable of driving transcription of a polycistronic transcript comprising said nucleic acid encoding said first polypeptide, an internal ribosome entry site (IRES), and said nucleic acid encoding said second polypeptide, and wherein said membrane anchoring polypeptide sequence comprises a polypeptide capable of a glycosylphosphatidyl-inositol (GPI) modification, and asserts that at no point does either combination of cited references teach or suggest that a person having ordinary skill in the art should make or use such a recombinant vaccinia virus. In fact, at no point do the combinations of cited references teach or suggest driving transcription of a polycistronic transcript comprising (a) nucleic acid encoding an IL-12p35 polypeptide sequence, (b) an IRES, and (c) nucleic acid encoding an IL-12p40 polypeptide sequence, a polypeptide linker, and a membrane anchoring polypeptide sequence comprising a polypeptide capable of a GPI modification (remarks, p3).
Applicant’s argument is fully considered but found not persuasive. Specifically, Bell et al. teach orthopoxvirus vectors comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM) ((parag 00508). Bell et al. teach using p35 subunit link to the transmembrane domain, but do not point out: (1) using the p40 subunit to link to a transmembrane domain; (2) having IRES between the two subunits (p35 and p40) in IL-12; and (3) the membrane anchoring polypeptide is capable of a glycosylphosphatidyl-inositol (GPI) modification. However, these were disclosed by Guo et al. at the time of instant invention.
Regarding (1) using p40 subunit instead of p35 subunit to link to a transmembrane domain, Guo et al. teach the p40 subunit (which exist in both IL-12 and IL-23) is structurally capable of linking to an anchoring peptide, optionally with a linker peptide between the p40 subunit and the anchoring peptide (see p32, L4-5). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising a p40 subunit (e.g., human IL-12 p40), a p35 subunit (e.g., human IL-12 p35) and a transmembrane domain link to p35 subunit (IL12-TMp70, or p40-p35-TM), and use the p40 subunit to link to the anchoring peptide with a linker, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (IL12-TMp70, or p40-p35-TM) is instant claim comprises a p40 subunit link to an anchoring peptide. Given that Guo et al. teach IL-23p40 are linked to an anchoring peptide, optionally with a linker peptide between IL-23p40 and the anchoring peptide (p32, L4-5), and Luo et al. provide evidence that IL-12 and IL-23 share a common p40 subunit (Abstract), one of ordinary skill in the art would have substituted IL-12p35 polypeptide sequence linked to the membrane anchoring polypeptide sequence (e.g., p40-p35-TM), and link p40 subunit to the membrane anchoring polypeptide sequence (e.g., p35-p40-TM), depends on the research interest and preferences.
Regarding (2) having IRES between the two subunits (p35 and p40), Guo et al. teach the IRES linker in the diagram of insertion, in vvDD thymidine kinase (tk) gene, of p7.5e/l viral promoter operably linked to murine IL-23p19-encoding nucleic acid fused to IRES linker and murine IL-23p40 anchor-encoding sequences, in virus denoted vvDD-mIL-23p19-IRES (p6, L8-11, figure 3). 23p19 and 23p40 are two subunits of IL-23. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and uses IRES to separate the nucleic acid encoding the first polypeptide (IL-12p35) and the nucleic acid encoding the second polypeptide (IL-12p40) by IRES as taught by Guo et al.. The skilled artisan would have been motivated to use IRES between the first and second polypeptide since Guo et al. teach IRES can be used in the construct comprising IL-23p19 and IL-23p40 (two subunits of IL-23, see p23, L24-26) for successfully expressing IL-23. There would be a reasonable expectation of success of using IRES in the recombinant vaccinia virus, since the sequence of IRES is well known in the art, and a skilled artisan has the knowledge for placing IRES between two nucleic acid sequences encoding two polypeptides in a construct.
Moreover, regarding (3) the membrane anchoring polypeptide is capable of a glycosylphosphatidyl-inositol (GPI) modification, Guo et al. teach an anchoring peptide (i.e., a GPI-anchor acceptor peptide) can be used to modify an immunomodulator molecule to bind to the membrane of the host cell. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (i.e., p35-p40-TM), and use an anchoring peptide having a glycosylphosphatidyl-inositol (GPI) modification as taught by Guo et al.. The skilled artisan would have been motivated to use a GPI modification since Guo et al. teach using GPI modification can modify an immunomodulator molecule to bind to the membrane of the host cell (see p24, L30-33), which is beneficial for the treatment (of e.g., a tumor cell). There would be a reasonable expectation of success of having a glycosylphosphatidyl-inositol (GPI) modification for the anchoring polypeptide, since Guo et al. teach engineered vaccinia virus with a GPI anchoring peptide (see p52, Example 1) and exemplary sequences of GPI modification (e.g., see p26 and p52).
In sum, the teaching of Bell et al. and Gao et al. render obvious to instant claims. Therefore the rejection is maintained and modified necessitated by Applicant’s amendment.
Modified rejections
Modified Objection to Drawing
The drawings are objected to because Applicant only submits a single replacement sheet but not includes all of the figures appearing on the immediate prior version of the sheet. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 8, 14, 15, 18 and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (WO 2020/124274 A1, internation filing date 12/20/2019, designated to US, with a priority date of 12/21/2018, cited in IDS), as evidenced by Hamza et al. (Int. J. Mol. Sci. 2010, 11, 789-806), in view of Guo et al. (WO 2018/145033 Al, published 09/08/2018, cited in IDS), as evidenced by Luo et al. (J Mol Biol. 2010 Oct 8;402(5):797-812). The rejection is modified necessitated by Applicant’s amendment.
Bell et al. teach modified orthopoxvirus vectors, as well as methods of using the same for the treatment of various cancers. The disclosure provides modified orthopoxvirus vectors that exhibit various beneficial therapeutic activities, including enhanced oncolytic activity, spread of infection, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, amenability for large scale manufacturing, and safety (Abstract).
Regarding claim 1, Bell et al. teach genetically modified orthopoxviruses, such as vaccinia viruses that exhibit mutations in one or more, or all, of these genes may exhibit an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and/or amenability for large scale manufacturing. In various embodiments, the modified orthopoxvirus expresses at least one of three transgenes: Interleukin 12 containing a transmembrane domain (IL-12-TM), PMS-like tyrosine kinase 3 ligand (FLT3-L) and anticytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) antibody (parag 0006). Bell et al. teach a second transgene comprising a second nucleotide sequence encoding an IL-12 polypeptide (parag 0031, also claim 11 in p686). In specific embodiments, the IL-12 polypeptide comprises IL-12 p35 or IL-12 p70 (parag 0018). In specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM) (parag 00508). The transmembrane domain can be derived from any membrane-bound protein (e.g., B7-1, membrane-bound TNFa, or membrane-bound FLT3L). The cytoplasmic domain can be derived from any protein that contains a cytoplasmic domain (e.g., B7-1, TNFa, or FLT3L) (parag 00508). Since Bell et al. teach IL-12 p70 comprises two subunits (IL-12 p35 subunit and IL-12 p40 subunit), the teaching indicates the nucleotide sequence encoding an IL-12 polypeptide would comprises nucleic acids encoding an IL-12p35 polypeptide sequence, and nucleic acids encoding an IL-12 p40 polypeptide sequence, reads on “a recombinant vaccinia virus comprising a vaccinia virus genome comprising (a) nucleic acid encoding a first polypeptide and (b) nucleic acid encoding a second polypeptide, wherein said first polypeptide comprises an IL-12 p35 polypeptide sequence, wherein said second polypeptide comprises an IL-12 p40 polypeptide sequence” in instant claim. Bell et al. teach IL-12 polypeptide comprises IL-12 p70 comprising a transmembrane domain and cytoplasmic domain, e.g., p40-p35-TM, indicates that IL-12 p35 subunit connecting to a membrane anchoring polypeptide sequence. Bell et al. teach claims 11-12, a nucleic acid comprising a recombinant vaccinia virus genome comprising a second transgene comprising a second nucleotide sequence encoding an Interleukin 12 (IL-12) polypeptide, further comprising a nucleotide sequence comprising at least one promoter operably linked to the second nucleotide sequence (see p686). The teachings indicate that the promoter is able to regulate the expression of both p35 subunit and p40 subunit, which reads on “a promoter capable of driving transcription of a polycistronic transcript that expresses said first polypeptide and said second polypeptide” as recited in instant claim. Instant claim differs from Bell et al. at:
instant claim has the second polypeptide comprises an IL-12p40 polypeptide sequence, a polypeptide linker, and a membrane anchoring polypeptide sequence (that is, the p40 subunit instead of p35 subunit links to a polypeptide linker and a membrane anchoring polypeptide sequence);
there is an internal ribosome entry site (IRES) between said nucleic acid encoding said first polypeptide (IL-12p35) and said nucleic acid encoding said second polypeptide ((IL-12p40);
said membrane anchoring polypeptide sequence comprises a polypeptide capable of a glycosylphosphatidyl-inositol (GPI) modification.
However, such were disclosed by Guo et al. at the time of instant claim.
Guo et al. teach tumor infiltrated T cells induced by oncolytic virus ("OV-induced T cells"), methods of making and using said OV-induced T cells for an adoptive T-cell therapy. The disclosed subject matter further relates to oncolytic viruses and armed oncolytic viruses, methods of making and using said oncolytic viruses, as well as pharmaceutical compositions and kits comprising said oncolytic viruses (Abstract).
Regarding (1), Guo et al. teach an oncolytic vaccinia virus, comprising, in its genome, a nucleic acid, which is a deoxyribose nucleic acid, encoding IL-23p19 and IL-23p40. In certain embodiments,
the IL-23p19 and IL-23p40 are linked to an anchoring peptide, optionally with a linker peptide between IL-23p40 and the anchoring peptide (p32, L4-5). It is known and evidenced by Luo et al. that interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit (Abstract). These teachings indicate that the p40 subunit is structurally available and capable of linking to a linker peptide and the anchoring peptide.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM), and use p40 subunit to link to the anchoring peptide with a linker, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (IL12-TMp70, or p40-p35-TM) is instant claim comprises a p40 subunit linking to the transmembrane domain (membrane anchoring peptide). Given that Guo et al. teach IL-23p40 are linked to an anchoring peptide, optionally with a linker peptide between IL-23p40 and the anchoring peptide (p32, L4-5), and Luo et al. provide evidence that IL-12 and IL-23 share a common p40 subunit (Abstract), one of ordinary skill in the art would have substituted IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence (e.g., p40-p35-TM), and link p40 subunit to the transmembrane domain (membrane anchoring peptide), depends on the research interest and preferences. This simple substitution of one known element (IL-12 having p40 subunit link to an membrane anchoring peptide) for another known element (IL-12 having p35 subunit link to an membrane anchoring peptide) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding (2) , Guo et al. teach diagram of insertion, in vvDD thymidine kinase (tk) gene, of p7.5e/l viral promoter operably linked to murine IL-23p19-encoding nucleic acid fused to IRES linker and murine IL-23p40 anchor-encoding sequences, in virus denoted vvDD-mIL-23p19-IRES (p6, L8-11, figure 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and uses IRES to separate the nucleic acid encoding the first polypeptide (IL-12p35) and the nucleic acid encoding the second polypeptide (IL-12p40) by IRES as taught by Guo et al.. The skilled artisan would have been motivated to use IRES between the first and second polypeptide since Guo et al. teach IRES can be used in the construct comprising IL-23p19 and IL-23p40 (two subunits of IL-23, see p23, L24-26) for successfully expressing IL-23. There would be a reasonable expectation of success of using IRES in the recombinant vaccinia virus, since the sequence of IRES is well known in the art, and a skilled artisan has the knowledge for placing IRES between two nucleic acid sequences encoding two polypeptides in a construct.
Regarding (3), Guo et al. teach in certain embodiments, the disclosed subject matter provides an oncolytic virus encoding a membrane-associated protein comprising an immunomodulator molecule linked to an anchoring peptide (p4, L10-13). In certain embodiments, the anchoring peptide comprises a GPI-anchor acceptor peptide or a PD-LI transmembrane domain (p4, L21-22). Guo et al. teach in certain embodiments, an anchoring peptide can be used according to the disclosed subject matter to modify an immunomodulator molecule to bind to the membrane of the host cell (e.g., by adding a GPI or other molecule).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use an anchoring peptide having a glycosylphosphatidyl-inositol (GPI) modification as taught by Guo et al.. The skilled artisan would have been motivated to use a GPI modification since Guo et al. teach using GPI modification can modify an immunomodulator molecule to bind to the membrane of the host cell (see p24, L30-33), which is beneficial for the treatment (of e.g., a tumor cell). There would be a reasonable expectation of success of having a glycosylphosphatidyl-inositol (GPI) modification for the anchoring polypeptide, since Guo et al. teach engineered vaccinia virus with a GPI anchoring peptide (see p52, Example 1) and exemplary sequences of GPI modification (e.g., see p26 and p52).
Regarding claim 7, Bell et al. do not teach said membrane anchoring polypeptide sequence is from about 10 amino acids to about 50 amino acids in length. However, Guo et al. teach in certain non-limiting embodiments, the anchoring peptide is between about 10 and about 50 amino acids, or between about 15 and about 30, or about 20 amino acids in length (p25, L1-3).
Regarding claim 8, Bell et al. do not teach said polypeptide capable of a GPI modification is derived from a CD16b polypeptide. However, Guo et al. teach in certain embodiments, the oncolytic virus can comprise a gene encoding a membrane-associated fusion protein that includes an immunomodulator molecule fused to an anchoring peptide, e.g., a GPI anchor (e.g., a GPI-anchor acceptor sequence of human CD16b)(p29, L13-16).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use an anchoring peptide capable of a glycosylphosphatidyl-inositol (GPI) modification (e.g., a GPI-anchor acceptor sequence of human CD16b) as taught by Guo et al.. The skilled artisan would have been motivated to use a GPI modification since Guo et al. teach using GPI modification can modify an immunomodulator molecule to bind to the membrane of the host cell (see p24, L30-33), which is beneficial for the treatment (of e.g., a tumor cell). There would be a reasonable expectation of success of having a glycosylphosphatidyl-inositol (GPI) modification for the anchoring polypeptide, since Guo et al. teach exemplary GPI anchoring peptide (e.g., a GPI-anchor acceptor sequence of human CD16b, see p29, L13-16).
Regarding claim 14, Bell et al. do not teach said polypeptide linker is from about one amino acid to about 25 amino acids in length. However, Guo et al. teach in certain embodiments, the peptide linker can, for example and not by way of limitation, be between about 1 and about 25 or between about 5 and about 20 or between about 5 and about 15 amino acids in length (p27, L28-30).
Regarding claim 15, Bell et al. do not teach said polypeptide linker comprises a (G4S)3 sequence (SEQ ID NO:13) or an A(EA3K)4AAA sequence (SEQ ID NO:14) sequence. However, Guo et al. teach in certain embodiments, the peptide linker comprises a flexible linker. In certain embodiments, the flexible linker can be (G4S)3 (p28, L1-2). In certain embodiments, the peptide linker comprises a rigid linker. In certain embodiments, the rigid linker can be (A(EA3K)4AAA)(p27, L12-13).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM), and use a polypeptide linker such as a (G4S)3 sequence or an A(EA3K)4AAA sequence between the IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (IL12-TMp70, or p40-p35-TM) is instant claim comprises a polypeptide linker such as a (G4S)3 sequence or an A(EA3K)4AAA sequence between the IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence. Given that Guo et al. teach alternatively the immunomodulator molecule can be linked to the anchoring peptide via a linker (p27, L21-22), one of ordinary skill in the art would have substitute IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence (e.g., p40-p35-TM), and use a linker between IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence, depends on the research interest and preferences. This simple substitution of one known element (using a polypeptide linker such as a (G4S)3 sequence or an A(EA3K)4AAA sequence between IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence) for another known element (IL-12p35 polypeptide sequence directly connect to the membrane anchoring polypeptide sequence) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 18, Bell et al. teach using a late promoter such as an Fl 7R promoter, or a Dl3L promoter (see p686, claims 13-14) for the IL-12 polypeptide, do not teach the promoter is selected from the group consisting of a p7.5 e/l promoter and a pSe/l promoter. However, Guo et al. teach in certain embodiments, the nucleic acid encoding IL-2 is operably linked to a promoter active or activatable in an oncolytic virus-infected cell, for example, an oncolytic virus promoter (e.g., a vaccinia virus promoter)(p30, L9-12). Guo et al. teach in certain embodiment, said encoding nucleic acid can be operably linked to a vaccinia promoter, for example the p7.5 e/1 promoter, or the pSe/1 promoter to generate a promoter-encoding construct (p30, L25-27).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use a promoter such as a p7.5 e/l promoter and a pSe/l promoter which is capable of driving transcription of the first polypeptide and the second polypeptide, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain is instant claim uses a promoter such as a p7.5 e/l promoter and a pSe/l promoter for the expression of IL-12 polypeptide. Given that Guo et al. teach using a vaccinia promoter such as the p7.5 e/1 promoter, or the pSe/1 promoter to generate a promoter-encoding construct (see p30, L25-27), one of ordinary skill in the art would have substituted Bell et al.’s late promoters such as an Fl 7R promoter or a Dl3L promoter, and use a vaccinia promoter such as the p7.5 e/1 promoter or the pSe/1 promoter for the expression of IL-12 polypeptide depends on their research interest or preference. This simple substitution of one known element (using a vaccinia promoter such as the p7.5 e/1 promoter or the pSe/1 promoter for the expression of IL-12 polypeptide) for another known element (using late promoters such as an Fl 7R promoter or a Dl3L promoter for the expression of IL-12 polypeptide) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 20, Bell et al. teach in specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM) (parag 00508). Bell et al. teach Examples 27, efficacy of SKV (vaccinia virus) expressing membrane bound IL-12p35-TM subunit versus IL12p70-TM subunit on tumor volume MC-38 mouse models (parag 00740). SKV-mIL12p35 and SKV-mIL12p70 treated mice showed comparable reductions in tumor volume (parag 00740). Bell et al. teach the function of IL12p70-TM, but do not specifically show the mechanism of IL12p70-TM. However, it is considered as an inherent property that IL-12p70 is a heterodimer of IL-12 p35 and IL-12 p40, and have the ability to stimulate an IL-12 receptor of another cell, which is evidenced by Hamza et al..
Hamza et al. provide evidence about the function and mechanism of IL-12p70. Hamza et al. teach that Interleukin 12 (termed IL-12p70 and commonly designated IL-12) is an important immunoregulatory cytokine that is produced mainly by antigen-presenting cells (Abstract), it is a heterodimeric cytokine (p790, parag 2). The biological activities of IL-12 are mediated via binding to a membrane receptor complex which is also composed of two subunits: IL-12R β1 and IL-12R β2 (p790, parag 5). This teaching reads on IL-12 p70 is in the form of a heterodimer having the ability to stimulate an IL-12 receptor of another cell, as recited in instant claim.
Claims 1, 2, 4, 7, 8, 14, 15, 18 and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (WO 2020/124274 A1, internation filing date 12/20/2019, designated to US, with a priority date of 12/21/2018, cited in IDS), as evidenced by Hamza et al. (Int. J. Mol. Sci. 2010, 11, 789-806), in view of Guo et al. (WO 2018/145033 Al, published 09/08/2018, cited in IDS), as evidenced by Luo et al. (J Mol Biol. 2010 Oct 8;402(5):797-812), as applied to claims 1, 7, 8, 14, 15, 18 and 20 above, further in view of Wagner et al. (US 2003/0105054A1, cited in IDS).
The teaching of Bell et al. and Guo et al. is set forth above.
Regarding claims 2 and 4, Bell et al. teach in specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (parag 0507). Bell et al. do not specifically point out whether the p40 subunit or p35 subunit is a full length polypeptide. However, it is prima facie obvious in view of Wagner et al..
Wagner et al. teach immunogenic compositions for stimulating T cell proliferation and methods for enhancing therapeutic effectiveness of some traditional anti-cancer treatments. Specifically, local delivery of cytokines that target the plasma membrane of a cancerous cell exhibit more potent anti-tumor effects than systemic delivery of cytokines in soluble form (Abstract).
Regarding claims 2 and 4, Wagner et al. teach an immunogenic composition containing a vector comprising a nucleic acid encoding a factor that stimulates T cell proliferation attached to a sequence that signals a GPI anchor is described. It is preferred that the vector of the immunogenic composition is a plasmid or a virus vector. Preferably, the virus is a conditionally replicating adenovirus. Also preferred, the factor that stimulates T cell proliferation is a cytokine. Still preferred, the cytokine is IL-2 or IL-12 (parag 0011). In Example 1, Wagner et al. teach GPI anchored IL-12 expression vectors: the murine IL-12 B (p40) cDNA subunit was inserted into pcDNA3.1(+)/Zeo expression plasmid between EcoRI/XhoI sites. The stop codon was removed by PCR and the GPI anchor Sequence was inserted in frame into the same plasmid between XhoI and Xbal. Additionally, murine IL-12A (p35) cDNA was inserted into another pcDNA3.1(+)/Zeo plasmid between EcoRI/Xho sites with stop codon on it. The entire fragment of p35 and the pCMV promoter was cut off by BglII/StuI and blunt ended with Klenow. This fragment was inserted into pcDNA3.1(+)/Zeo-IL12-B-GPI plasmid which was cut with BglII and blunt ended with Klenow. The new recombinant plasmid was named pL12-A-BGPI and contains both the A and B subunit of IL-12, in which A is secreted and B is linked with a GPI anchor sequence (parag 0076). This GPI anchored IL-12 expression vector uses the cDNAs of IL-12 p40 and IL-12 p35 for expressing both the p35 and p40 subunit of IL-12, reads on “said IL-12p35 polypeptide sequence is a human IL-12p35 polypeptide sequence or a full length mouse IL-12p35 polypeptide sequence” in instant claim 2, and “ said IL-12p40 polypeptide sequence is a full length human IL-12p40 polypeptide sequence or a full length mouseIL-12p40 polypeptide sequence” in instant claim 4.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use a full length IL-12 p35 polypeptide sequence and a full length IL-12 p40 polypeptide sequence for encoding the IL-12 polypeptide comprises IL-12 p70, as taught by Wagner et al.. The skilled artisan would have been motivated to use the full length IL-12p35 polypeptide sequence (IL-12p35 cDNA) and IL-12p40 polypeptide sequence (IL-12p35 cDNA) for expressing IL-12, since Wagner et al. teach the IL-12 expression vector using IL-12 35p cDNA and IL-12 40p cDNA for successfully expressing functional IL-12 (see Examples). There would be a reasonable expectation of success of using a full length IL-12p35 polypeptide sequence and a full length IL-12p40 polypeptide sequence since Wagner et al. teach using the cDNAs of IL-12p35 and IL-12p40 for the IL-12 expression vector (Example 1), also the IL-12p35 cDNA and IL-12p40 cDNA was publicly accessible (e.g., GenBank).
Conclusion
No Claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699